A post-hoc analysis of the SHIFT study found a 32% reduction in the risk of cardiovascular death or hospitalization for worsening heart failure among patients on ivabradine who weren't taking beta blockers compared with those on placebo (P=0.003), according to John Cleland, MD, of Royal Brompton Hospital in England, and colleagues.

"When looking at the outcomes of this analysis, there seems to be a greater impact among patients on ivabradine who were not taking a beta blocker," Cleland said at the European Society of Cardiology meeting. "In contrast with the main study, this was driven equally by hospitalization for worsening heart failure and cardiovascular death/all-cause mortality."

The main trial, reported in The Lancet in 2010, showed that treatment with ivabradine reduced cardiovascular death and hospitalization for worsening heart failure better than placebo – an 18% reduction in events (P<0.0001) -- and in all-cause mortality – a 20% reduction (P=0.002). The study compared ivabradine with placebo among heart failure patients who had heart rates above 70 beats per minute. Cleland noted in that study, the primary outcome was mainly driven by the need for hospitalization due to worsening heart failure.

"Ivabradine does reduce mortality in patients who are unable or unwilling to take beta blockers," he said. "There are a large number of patients with heart failure who are managed without beta blockers."

Clyde Yancy, MD, professor and chief of cardiology at Northwestern University who wasn't involved in the study, called the analysis "important," noting that it explores a "question that has been plaguing us for a little bit – how do we treat patients with heart failure who cannot tolerate beta blockers?"

"This is an ideal way to answer the question, by using a heart rate drug in the absence of a beta blockers," Yancy said. "Ten percent of the patients in the study were not on beta blockers. While the numbers are small, it is not uncommon in clinical practice to encounter a patient who cannot tolerate a beta blocker."

"The SHIFT investigators have made a very compelling case that modulating heart rate is a reasonable target and ought to be a benefit," he added. "This exercise indicates that heart rate is important. Testing this would be reasonable strategy to pursue. While the quality of the data is quite good, this still reflects a post-hoc analysis with a non-specified outcome."

Yancy noted that for physicians treating heart failure, "our use of ivabradine has been modest at best, but we all see the patients who, for a variety of reasons, aren't able to take beta blockers. It is intriguing to think about ivabradine in this space – particularly with heart rate as a predictor. It is informative and has a clinical utility. I think it sets us up nicely for new directions that we should exploit."

The analysis included 635 patients who were not taking beta blockers. "They were slightly older, had greater ethnic diversity, had a lower body mass index, had more lung disease than people treated with beta blockers, and these factors are usually associated with adverse prognosis," Cleland said. "They had more advanced symptoms and they had a higher heart rate, worse renal function, and much more use of digoxin rather than a beta blocker. More than 50% of the patients who were not on a beta blocker had a resting heart rate in sinus rhythm or 80 beats per minute."

Cleland noted that beta blockers are a highly effective treatment for heart failure in patients with reduced ejection fraction, but the mechanism for this remains uncertain, and it might simply be due to heart rate reduction. Currently, ivabradine is only recommended as an additive to beta blockers rather than an alternative to them.

"I think that this is an interesting, hypothesis-generating analysis and we do need more information," he said. "I think there should be a trail to evaluate ivabradine in patients who do not take beta blockers. I think there is an onus on the cardiology community to do such a trial. This is not enough information to change guidelines, but this is enough information to require validation in a new study."

The SHIFT study was funded by Servier; the current analysis was not funded.

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